WO2002072567A2 - Nouveaux composes heterocycliques utiles dans le traitement des troubles allergiques inflammatoires; procede de leur preparation et compositions pharmaceutiques les contenant - Google Patents

Nouveaux composes heterocycliques utiles dans le traitement des troubles allergiques inflammatoires; procede de leur preparation et compositions pharmaceutiques les contenant Download PDF

Info

Publication number
WO2002072567A2
WO2002072567A2 PCT/US2002/007315 US0207315W WO02072567A2 WO 2002072567 A2 WO2002072567 A2 WO 2002072567A2 US 0207315 W US0207315 W US 0207315W WO 02072567 A2 WO02072567 A2 WO 02072567A2
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
formula
hydrogen
lower alkyl
Prior art date
Application number
PCT/US2002/007315
Other languages
English (en)
Other versions
WO2002072567A3 (fr
Inventor
Duvvuri Subrahmanyam
Sunil Vasantrao Mali
Gopalan Balasubramanian
Aftab Dawoodbhai Lakdawala
Original Assignee
Glenmark Pharmaceuticals Limited
Mass, Clifford, J.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glenmark Pharmaceuticals Limited, Mass, Clifford, J. filed Critical Glenmark Pharmaceuticals Limited
Priority to AU2002306687A priority Critical patent/AU2002306687A1/en
Publication of WO2002072567A2 publication Critical patent/WO2002072567A2/fr
Publication of WO2002072567A3 publication Critical patent/WO2002072567A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel heterocyclic compounds, their analogs, their tautomers, their regioisomers, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and their pharmaceutical compositions containing them.
  • the present invention more particularly relates to novel PDE4 inhibitors of the formula 1, their analogs, their tautomers, their regioisomers, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and the pharmaceutical compositions containing them.
  • the present invention also relates to a process for the preparation of the above said novel compounds of the formula 1 as defined below.
  • TNF- ⁇ Tumor necrosis factor
  • This second messenger is regulated by the phosphodiesterase(PDE) family of enzymes.
  • the phosphodiesterase enzymes play an integral role in cell signaling mechanisms by hydrolyzing cAMP and cGMP to their inactive 5' forms. Inhibition of PDE enzymes thus results in an elevation of cAMP and /or cGMP levels and alters intracellular responses to extra cellular signals by affecting the processes mediated by cyclic nucleotides. Since eosinophils are believed to be a critical proinflammatory target for asthma, identification of the expression of PDE 4 gene family in eosinophils led to the PDE 4 as potential therapeutic target for asthma [ Rogers.D.F., Giembycz.M.A.,
  • the mammalian cyclic nucleotide phosphodiesterases(PDEs) are classified into ten families on the basis of their amino acid sequences and/or
  • Phosphodiesterase type 4 is an enzyme which regulates activities in cells which lead to inflammation in the lungs.
  • PDE4 a cAMP- specific and Ca -independent enzyme, is a key isozyme in the hydrolysis of cAMP in mast cells, basophils, eosinophils, monocytes and lymphocytes.
  • the association between cAMP elevation in inflammatory cells with airway smooth muscle relaxation and inhibition of mediator release has led to widespread interest in the design of PDE4 inhibitors [ Trophy,T ., Am.J.Respir. Crit. Care Med., 157, 351 -370( 1998)].
  • TNF-a production has been implicated in mediating or exacerbating a number of undesirable physiological conditions such as diseases including osteoarthritis, and other arthritic conditions; septic shock, ecdotoxic shock, respiratory distress syndrome, bone resorption diseases. Since TNF- ⁇ also participates in the onset and progress of autoimmune diseases, PDE4 inhibitors may find tremendous utility as therapeutic agents for rheumatoid arthritis, multiple sclerosis and Crohn's disease. [Nature Medicine, J_, 211-
  • TNF- ⁇ is also reported to be a factor of insulin-resistant diabetes because it declines the phosphorylating mechanism of insulin receptors of muscle and fat cells [ J.clin.Invest, 94 ⁇ 1543-
  • PDE-4 strongly suggested that the pathologies related to the central nervous and immune systems could be treated through the selective PDE 4 inhibitors (b) the increase in intracellular cAMP concentration, the obvious biochemical consequence of PDE-4 inhibition, has been well characterized in immuno-competent cells where it acts as a deactivating signal.
  • PDE4-A,B,C,D human cDNA isoforms of PDE-4
  • mRNA for all these four isoforms was expressed in human lungs.
  • PDE 4-A, B and D were expressed in eosinophils.
  • PDE-4 characterized as the cAMP-specific gene family has been shown to predominate in pro-inflammatory human lymphoid and myeloid lineage cells. It has been demonstrated that increasing cAMP levels within these cells results in suppression of cell activation which in turn inhibits the production and release of pro-inflammatory cytokines such as TNF-. Since eosinophils are believed to be a critical pro-inflammatory target for asthma, identification of the expression of PDE 4 gene family in eosinophils led to the PDE 4 as potential therapeutic target for asthma.
  • PDE4 There exist two binding sites on mammalian PDE4 at which inhibitor molecules bind. Also PDE4 exists in two distinct forms which represent different conformations. They are designated as High affinity Rolipram binding site PDE4H and Low affinity Rolipram binding site PDE4L[ Jacobitz,S., McLaughlin,M.M., Livi,G.P., Burman,M., Trophy,T.J., Mol. Pharmacol .,50, 891-899(1996)]. It was proved that certain side effects (vomiting and gastric acid secretion) are associated with inhibition of PDE4H whereas some beneficial actions are associated with PDE4L inhibition.
  • n represents an integer of 1 to 4;
  • R 1 , R 2 , R 3 and R 4 are the same or different and represent hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, polycycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, or substituted or unsubstituted aralkyl, or two groups present on the same carbon atom among R 1 , R 2 , R 3 and R 4 are combined to represent a saturated carbon ring, two groups present on the adjacent carbon atoms among R 1 , R 2 , R 3 and R 4 are combined to represent a saturated carbon ring, together with the two carbon atoms adjacent thereto, or two groups present on the adjacent carbon atoms among R 1
  • X represents -CR R (wherein R and R are the same or different and represent hydrogen, substituted or unsubstituted lower alkyl, cycloalkyl, polycycloalkyl, substituted or unsubstituted lower alkenyl, cycloalkenyl, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted lower alkanoyl, cycloalkylcarbonyl, lower alkoxycarbonyl, or cyano, or represent a single bond together with R 8 ), S, NR 13 (wherein R 13 represents hydrogen, substituted or unsubstituted lower alkyl, cycloalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, or substituted or unsubstitued aralkyl, or represents a single bond together
  • R are combined to represent a substituted or unsubstituted heterocylic group; and m represents an integer of 1 to 4); or (d) -Y- CON(R 17a )R 17b (wherein Y has the same meaning as defined above; and R 17a and R are the same or different and represent hydrogen, or substituted or unsubstituted lower alkyl, or R 17a and R I7b are combined to represent a substituted or unsubstituted heterocyclic group), or a pharmaceutically acceptable salt thereof.
  • R is hydrogen, acyl, lower alkyl, or -CHO, -CH 2 OR ⁇ 0 , -CO-R 7 ,or OR 13 ;
  • R 2 , R 3 , R 4 are independently hydrogen, lower alkyl, lower alkoxy, or halogen, ;
  • R 5 and R ⁇ are independently hydrogen or lower alkyl;
  • R 7 is hydroxy, lower alkoxy, or NR 8 R 9 ;
  • R 8 and R 9 are independently hydrogen, or lower alkyl;
  • X and Y are independently >CR ⁇ 4 ,R ⁇ 5 , -0-, -S-, >SO, >S0 2 or >NRi 8 ;
  • Rio and Rig are independently hydrogen, lower alkyl or acyl ;
  • M is - -CONH-, or -NH-CO- ;
  • R ⁇ , R 12 , R H and R 15 are independently hydrogen or lower alkyl
  • the compounds of the present invention are useful as therapeutic agents for inflammatory allergic diseases particularly bronchial asthma, allergic rhinitis and nephritis.
  • Tumor Necrosis factor(TNF) Tumor Necrosis factor
  • TNF Tumor Necrosis factor
  • autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, Crohn's disease, psoriasis ; diseases of the central nervous system such as depression amnesia, and dermentia cardiac failure, shock, and cerebrovascular disease and the like ; insulin-resistant diabetes and the like.
  • R a , R b , R c or R d may be the same or different and represent hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, polycycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aralkyl group or two groups present on the same carbon atom among R a , R b , R c , R d may be combined to represent a optionally substituted 5-8
  • R e represents hydrogen, halogen, nitro, alkylamino, hydroxyl, substituted or un substituted lower alkyl, substituted or unsubstituted lower alkoxy or two moieties of R e adjacent to each other are combined together to form a 5-6 membered cyclic ring optionally containing one hetero atom such as oxygen or nitrogen;
  • R gl and R g2 are independently hydrogen, hydroxyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy groups; m is an integer of 0, 1 or 2; and
  • R J represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl groups
  • W represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic groups
  • R 1 is a -(CH )s-Z-Ar 1 wherein Ar 1 is hydrogen, an optionally substituted monocyclic or bicyclic heteroaryl, substituted or unsubstituted aryl; Z is a bond, -0-, -S-, or NR 1 wherein R 1 represents hydrogen, substituted or unsusbstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted
  • R J represents hydrogen, substituted or unsubstituted lower alkyl, , substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl groups ;
  • R k represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl groups
  • R 1 is a group -(CH 2 )s-Z-Ar 1 wherein Ar 1 is hydrogen, an optionally substituted mono-cyclic or bicyclic heteroaryl , substituted or unsubstituted aryl);
  • Z is a bond, -0-, -S-, or NR 1 wherein R 1 represents hydrogen, substituted or unsusbstituted lower alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
  • s is an integer of 0 to 4 ; and W represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic groups; (4) a group represents -CH(R 1 )-L-W wherein L represents -N(R')-,
  • R 1 represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl groups and r is an integer of 0,1 or 2 ;
  • W represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic groups and R 1 is a - (CH 2 )s-Z-Ar 1 wherein Ar 1 is hydrogen, an optionally substituted monocyclic or bicyclic heteroaryl , substituted or unsubstituted aryl; Z is a bond, -0-, - S-, or N(R') (wherein R 1 represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or
  • a group represents -CONH-(CH 2 ) t -Ar 2 where t is 0 to 4 and Ar 2 represents substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubsituted cycloalkyl, substituted or unsubstituted heterocyclic groups;
  • the present invention particularly provides novel heterocyclic compounds of the formula 1
  • R a , R b , R c , R d , R e , R 1 , R 2 and W have the meanings described above.
  • the definition of the groups in the formula 1, their analogs, their tautomers, their regioisomers, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and their pharmaceutical compositions containing them have the following meanings throughout the present invention.
  • lower alkyl denotes a univalent, branched or straight hydrocarbon chain containing 1 to 8 carbon atoms. Representative of the alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec.butyl, tert.butyl, pentyl, iso pentyl, tert.pentyl, hexyl, isohexyl, octyl and the like.
  • the term 'lower alkoxy' denotes lower alkyl groups as defined above attached via oxygen linkage to the rest of the molecule. Representative of those groups are methoxy, ethoxy, isopropoxy, tert.butoxy, hexoxy, heptoxy, octoxy and the like.
  • 'cycloalkyl denotes having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
  • polycycloalkyl denotes having 4 to 12 carbon atoms, such as bicyclo[3.2.1]octyl, bicyclo[4.3.2]undecyl, adamantyl and noradamantyl and the like.
  • lower alkenyl' includes straight-chain or branched alkenyl groups having 2 to 8 carbon atoms, such as vinyl, 1-propenyl, allyl, methacryl, 1-butenyl, crotyl, pentyl, isoprenyl, hexenyl, heptenyl, and octenyl.
  • 'cyclo alkenyl' includes cycloalkenyl groups having 4 to 10 carbon atoms, such as cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl and cyclodecenyl.
  • 'aryl' includes phenyl and naphthyl and the like.
  • 'aralkyl' includes aralkyl groups having 7 to 15 carbon atoms, such as benzyl, phenethyl, and naphthylmethyl and the like.
  • heteroaryl' group represented in compounds of formula 1 may preferably be selected from pyridyl, quinoline, isoquinoline, indanyl, pyrrole, furan, thiophene, pyrimidine, pyridazinyl, benzofuryl, isobenzofuryl, benzothienyl, indolyl, isoindolyl, benzimidazolyl, benzothiazolyl, quinazolinyl, naphthyridinyl, pyrrolyl, imidazole, benzimidazole, triazine, oxazole, benzoxazole, isoxazole, thiazole, benzathiazole, thiazolidine, and the like.
  • heterocyclic' group includes 5-,6- or 7-membered monocyclic heterocyclic groups and condensed heterocyclic groups comprising a 6-membered ring and another 6-memered ring, such as pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino, homopiperidino, homopiperazinyl, tetrahydropyridinyl, tefrahydroquinolinyl, and tetrahydroisoquinolinyl and the like.
  • 'halogen' or 'halo' represents fluorine, chlorine or bromine and the like.
  • the substituents in the term 'substituted lower alkyl' group may be the same or different which are selected fiOm lower alkenyl; substituted or unsubstituted cycloalkyl or heterocycloalkyl; substituted or unsubstituted aryl or heteroaryl groups; substituted or unsubstituted cycloalkoxy or heterocycloalkoxy; substituted or unsubstituted phenoxy or aryloxy; substituted or unsubstituted benzyloxy; substituted or unsubstituted lower alkoxy; hydroxyl, formyl, aldoxime, carboxyl, alkoxycarbonyl, lower alkanoyl, substituted or unsubstituted benzoyl; OS0 2 R' where R' denotes lower alkyl or aryl groups; halogen, haloalkoxy, cyano, nitro, amino or amido in which the amino group may be mono or di substituted where both the substitutent
  • the substituents in the term 'substituted lower alkenyl' group may be the same or different which are selected from substituted or unsubstituted cycloalkyl or heterocycloalkyl; substituted or unsubstituted aryl or heteroaryl groups; substituted or unsubstituted cycloalkoxy or heterocycloalkoxy; substituted or unsubstituted phenoxy or aryloxy; substituted or unsubstituted benzyloxy; substituted or unsubstituted lower alkoxy; hydroxyl, carboxyl, alkoxycarbonyl, lower alkanoyl, substituted or unsubstituted benzoyl; OSO 2 R 1 where R' denotes lower alkyl or aryl groups; halogen, haloalkoxy, cyano, nitro, amino or amido where the amino group may be mono or di substituted in which both the substitutents may be independent or combined together to form a cyclic
  • 'substituted lower alkoxy' denotes 'substituted lower alkyl groups' as defined above attached via oxygen linkage to the rest of the molecule.
  • Representative examples of those groups are 2-hydroxyethoxy, 2- methoxyethoxy, 3-cyanopropoxy, 2-N,N-dimethylaminoethoxy, 3-N,N- diethylaminopropoxy, 4-nitrobutoxy, 2-pyr ⁇ olidino-ethoxy, 3- piperidinopropoxy, 2-cyclopropylethoxy, 3-fluoropropoxy, 2-[3'- nitrophenyl] ethoxy, 2-[3-N-methylaminophenyl]ethoxy and the like.
  • substituted amino' group used in the present invention refers to amino groups substituted with substituents which can be selected from the groups such as hydroxyl, substituted or unsubstituted lower alkyl, S0 2 R" where R" denotes lower alkyl or aryl group; substituted or unsubstituted benzyl or benzoyl; alkoxy, alkoxycarbonyl, amido, amino, alkylamino.
  • substituents can be selected from the groups such as hydroxyl, substituted or unsubstituted lower alkyl, S0 2 R" where R" denotes lower alkyl or aryl group; substituted or unsubstituted benzyl or benzoyl; alkoxy, alkoxycarbonyl, amido, amino, alkylamino.
  • substituents which can be selected from the groups such as hydroxyl, substituted or unsubstituted lower alkyl, S0 2 R" where R" denotes lower alkyl or aryl
  • both the substituents on the amino group can be combined together to form 5 or 6 membered cyclic ring system represented by pyrrolidino, piperdino, morphilino,piperazino, imidazolino and thiazolidino.
  • the substituents in the 'substituted cycloalkyl', and 'substituted cycloalkenyl' may be the same or different which are selected from groups such as lower alkyl, lower alkenyl, lower alkoxy, hydroxyl, alkoxycarbonyl, carboxyl, -CONHOH group, 5-membered heterocycles optionally containing hetero atoms such as oxygen, nitrogen, sulfur; phenyl, cyano, nitro, and halogen in which the lower alkyl, lower alkenyl, lower alkoxy and halogen each have the same meanings as defined above.
  • the substituents in the 'substituted aryl', 'substituted aromatic heterocyclic' group, 'substituted heterocyclic' group and 'substituted aralkyl' group may be the same or different which are selected from groups such as lower alkyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, SO 2 R" where R" denotes lower alkyl or aryl group; haloalkyl, carboxyl, -CONHOH; 5- membered heterocycles optionally containing hetero atoms such as oxygen, nitrogen, sulfur; carbamoyl, trifluoromethyl, amido, cyano, nitro, halogen, amino where the amino group may be mono or di substituted in which both the substitutents are independent or combined together to form a cyclic ring system of a total of 5-6 atoms containing carbon and optionally one or two hetero atoms selected from oxygen, nitrogen or sulfur.
  • the group R 1 is represented by -(CH 2 )s-Z-Ar 1 group;
  • the representative of such groups may be for example: -Ar, (-CH 2 ) 3 OAr 1 , -CHz-S-Ar 1 , -(CF S-Ar 1 , -(CH 2 -N(R h )-Ar 1 , -(CH 2 ) 2 -N(Rh)- Ar 1 or -(CH 2 ) 3 -N(R b )-Ar 1 and the like where Ar'.Rh & Rb are as defined earlier.
  • salts means non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
  • Representative salts include acetate, ascorbate, benzenesulfonate, benzoate, bicarbonate, borate, bromide, calcium edetate, carbonate, chloride, citrate, dihydrochloride, edetate, mesylate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxyapthoate, iodide, isothionate, ⁇ - ketoglutarate, ⁇ -glycerophosphate, glucose- 1 phosphate lutarate lactate, lactobionate, laurate, malate, methane-sulphate, maleate, mande
  • the compounds according to the invention can contain one or more asymmetrically substituted carbon atoms.
  • the presence of one or more of these asymmetric centers in compounds of formula 1 can give rise to stereoisomers and in each case the invention is to be understand to extend to all such stereoisomers, including enantiomers and diastereoisomers and their mixtures, including racemic mixtures.
  • the invention may also contain E & Z geometrical isomers wherever possible in the compounds of general formula 1 which includes the single isomer or mixture of both the isomers.
  • the invention also envisages within its scope the polymorphs and the analogs of the compounds of the general formula 1 as defined above .
  • Some of the representative compounds according to the present invention are specified below: 1 ) 0-(4-Methoxybenzoyl)-3-ethoxymethyl-2,3-dihydrobenzodioxin-6- yl phenyl ketoxime
  • the present invention also relates to a process for the preparation of the novel compound of formula JL
  • Ar 1 is an hydrogen, optionally substituted monocyclic or bicyclic heteroaryl, substituted or unsubstituted aryl, Z is a bond, -0-, -S-, or NR 1 and s is zero or the integer l,2,3,or 4; and R 1 represents hydrogen, substituted or unsubstituted loweralkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl groups, in the presence of alkyl lithium or Mg/Li metal and ethereal or aromatic solvents at a temperature in the range of -70 to 80° C to obtain the novel hydroxyl compounds of the general formula 10
  • Q represents -CE ⁇ R ⁇ -L-W wherein L represents -N(R')-, S(0)r-, - O- in which R 1 represents hydrogen, substituted or unsubstituted lower alkyl group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl group ; r is an integer of 0,1 or 2 and; W represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic groups and R 1 represents hydrogen, which comprises,
  • Q represents -CH(R 1 )-L-W wherein L represents -N(R')-, S(0)r-, - O- in which R 1 represents hydrogen, substituted or unsubstituted lower alkyl group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl group ; r is an integer of 0,1 or 2 and; W represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic groups and R 1 represents hydrogen, X, R a to R e have the meaning described above.
  • Q represents -C(R')(R 2 )-(CHR j )-W; wherein W is hydrogen, substituted or unsub-stiruted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic groups and R 1 is a group -(CH 2 )s-Z-Ar 1 wherein Ar 1 is hydrogen, an optionally substituted monocyclic or bicyclic heteroaryl , substituted or unsubstituted aryl; Z is a bond, -0-, -S-, or NR 1 wherein R 1 represents hydrogen, substituted or unsusbstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl groups and s is an integer of 0 to 4; R represents hydroxyl, substituted or unsubstituted lower al
  • R 1 represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl , substituted or unsubstitued heteroaryl groups, in the presence of alkyl lithium or Mg/Li metal and an ethereal or aromatic solvents at a temperature in the range of -
  • R a to R e have the meaning given above and where R 2 represents hydroxyl group and R J , R*& W have the meanings given earlier,
  • W is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic groups and R 1 is a group -(CH 2 )s-Z-Ar 1 wherein Ar' is hydrogen, an optionally substituted monocyclic or bicyclic heteroaryl , substituted or unsubstituted aryl; Z is a bond, -O-, -S-, or NR 1 wherein R 1 represents hydrogen, substituted or unsusbstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl groups and s is an integer of 0 to 4; R J represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsub
  • R 1 represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl , substituted or unsubstitued heteroaryl groups, in the presence of alkyl lithium or Mg/ Li metal and an ethereal or aromatic solvents at a temperature in the range of - 70 to 80° C to obtain the novel hydroxy compounds of the general formula 10 ,
  • R J denotes hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl groups
  • X, R a to R e , R 1 and W have the meaning described above
  • Q represents a group -CONH-(CH 2 ) t -Ar 2 where t is 0 to 4 and Ar 2 represents substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubsituted cycloalkyl, substituted or unsubstituted heterocyclic groups, which comprises, reacting the compounds of the formula 9
  • Q represents a group -CONH-(CH 2 ) t -Ar 2 where t is 0 to 4 and Ar 2 represents substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubsituted cycloalkyl, substituted or unsubstituted heterocyclic groups and X, R a to R e have the meaning described above ;
  • Q represents -CH(R 1 )-L-W (wherein L represents -N(R')-, S(0)r-, - O- in which R 1 represents hydrogen, substituted or unsubstituted lower alkyl group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl group ; r is an integer of 0,1 or 2 and; W represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic groups and R 1 is a group -(CH 2 )s-Z-Ar wherein Ar 1 is hydrogen, an optionally substituted monocyclic or bicyclic heteroaryl , substituted or unsubstituted aryl; Z is a bond, -O-, -S-, or NR 1 ,
  • R a to R e have the meanings described above, with a group
  • R ! -J where J is halogen other than fluorine and R 1 is a -(CH 2 )s-Z-Ar' group, where Ar 1 is an hydrogen, optionally substituted monocyclic or bicyclic heteroaryl, substituted or unsubstituted aryl, Z is a bond, -0-, -S-, or NR 1 and s is zero or the integer 1 ,2,3, or 4; and R 1 represents hydrogen, substituted or unsubstituted loweralkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl groups, in the presence of alkyl Lithium or Mg/ Li metal and ethereal or aromatic solvents at a temperature in the range of -70 to 80° C to obtain the novel hydroxy compounds of the general formula 10 ,
  • Q represents -CH(R 1 )-L-W wherein L represents -N(R')-, S(0)r-, - O- in which R 1 represents hydrogen, substituted or unsubstituted lower alkyl group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl group ; r is an integer of 0,1 or 2 and; W represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic groups and R 1 is a group -(CH 2 )s-Z-Ar 1 wherein Ar 1 is hydrogen, an optionally substituted monocyclic or bicyclic heteroaryl , substituted or unsubstituted aryl; Z is a bond, -0-, -S-, or NR 1 and s represents
  • R a , R b , R c , R d and R e have the meaning described above, which are employed in the above processes of the present invention are in general known compounds and may be prepared by the conventional methods reported in the literature.
  • the ethereal solvents used in the above described processes for the preparation of compounds of the formula 1 are selected from diethyl ether, 1 ,2-dimethoxyethane, tetrahydrofuran, diisopropyl ether, 1 ,4 dioxane and the like.
  • the chlorinated solvent which may be employed may be selected from dichloromethane, 1 ,2-dichloroethane, chloroform, carbontertrachloride and the like.
  • the aromatic solvents which may be employed may be selected from benzene, toluene.
  • the alcoholic solvents which may be employed may be selected from methanol, ethanol, n- propanol, iso propanol, tert.butanol and the like .
  • the aprotic solvents which may be employed may be selected from acetonitrile, N,N- dimethylformamide, dimethyl sulfoxide and the like.
  • the bases which may be employed in the above processes for the preparation of the compounds of the formula 1 are selected from carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate; hydride bases such as sodium hydride, potassium hydride; inorganic bases such as potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium tert.amyloxide, sodium methoxide, potassium tert.butoxide, or organic bases such as lithiumdiisopropylamide, lithiumhexmethyldisilazide; alkyl lithium bases such as n-butyl lithium, sec.butyl lithium, tert.butyl lithium and the like.
  • polymorphs of a compound of general formula 1 forming part of this invention may be prepared by crystallization of compound of formula 1 under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • the present invention also provides pharmaceutical compositions, containing compounds of the general formula 1, as defined above, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates in combination with the usual pharmaceutically employed carriers, diluents and the like.
  • the pharmaceutical compositions according to this invention can be used for the treatment of allergic disorders.
  • compositions may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like and may contain flavorants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions.
  • Such compositions typically contain from 1 to 20 %, preferably 1 to 10 % by weight of active compound of the formula 1 , the remainder of the composition being pharmaceutically acceptable carriers, diluents or solvents.
  • Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions.
  • the active compounds of the formula 1 will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above.
  • the compounds of the formula 1 can be combined with a suitable solid, liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like.
  • the pharmaceutical compositions may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like.
  • the compounds of the formula 1 can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
  • injectable solutions or suspensions for example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or salts with base of the compounds of the formula 1 .
  • injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.
  • the compounds of the formula 1 can be dispensed through inhaler in the form of drug powder, as well as pharmaceutically acceptable acid addition salts or salts with base or the compounds of the formula 1.
  • Step 1 Initially 3-hydroxymethyl-6-formyl-2,3-dihydrobenzodioxane was prepared from 3,4-dihydroxy benzaldehyde as described in the step-1 of
  • Step l Initially 3-hydroxymethyl-6-formyl-2,3-dihydrobenzodioxane was prepared from 3,4-dihydroxybenzaldehyde as described in step 1 of
  • Step 2 The 3 -methanesulfonyloxymethyl-6-formyl-2,3 -dihydrobenzodioxane (25g, 0.091mol) was refluxed in p-xylene (200mL) along with N,N- diethylamine (67.1mL) for 24h.
  • Step 3 A solution of 3,5-dichloropyridin-4-one (280mg, 1.1 equiv) dissolved in 20mL of N,N-dimethylformamide was treated with 500mg of potassium carbonate followed by a solution of 3-ethoxymethyl-6-chloromethyl-2,3- dihydrobenzodioxane( 500mg) in 5mL of N,N-dimethylformamide.
  • the reaction mixture was heated to 80°C for 2hrs and the poured into water. Extracted the aqueous layer with ethyl acetate and washed the organic layer with water, brine solution and dried over anh. sodium sulfate.
  • Step 1 3-Ethoxymethyl-6-formyl-2,3-dihydrobenzodioxane (4.8gm,0.021M) dissolved in diethyl ether(50mL) was treated with lithium aluminium hydride (2.0 gm,.,) at 0°C and the contents were stirred for 1.5h by allowing the temperature to warm to 25°C. Reaction was quenched with acetone(2mL) and evaporated the solvents to dryness under vacuum. Diluted the residue with 60mL of ether and extracted the organic layer with water and brine solution and dried over anhydrous sodium sulfate.
  • lithium aluminium hydride 2.0 gm,.,
  • Step 2 3 -Ethoxymethyl-6-chloromethyl-2,3 -dihydrobenzodioxane was prepared from 3-ethoxymethyl-6-hydroxymethyl-2,3-dihydrobenzodioxane as described in the step-2 of the Example 1. Step 3
  • 3-Ethoxymethyl-6-chloromethyl-2,3-dihydrobenzodioxane was prepared from 3-ethoxymethyl-6-hydroxymethyl-2,3-dihydrobenzodioxane as described in the step-2 of the Example 1.
  • Step 1 Initially 1 -[3-ethoxymethyl-2,3-dihydrobenzodioxan-6-yl]- 1 -phenyl methanol was prepared from 3-ethoxymethyl-6-formyl-2,3- dihydrobenzodioxane as described in step-1 of the Example-5. Step 2
  • 3-Ethoxymethyl-2,3-dihydrobenzodioxan-6-yl phenyl ketone was prepared from 1 - [3 -ethoxymethyl-2,3 -dihydrobenzodioxan-6-yl]- 1 -phenyl methanol as described in the step-2 of Example 5.
  • Step 3 3-Ethoxymethyl-2,3-dihydrobenzodioxan-6-yl phenyl ketoxime was prepared from 3-ethoxymethyl-2,3-dihydrobenzodioxan-6-yl phenyl ketone as described in step-3 of the Example-5.
  • Step 1 Initially 1 -[3-ethoxymethyl-2,3-dihydrobenzodioxan-6-yl]- 1 -phenyl methanol was prepared from 3-ethoxymethyl-6-formyl-2,3- dihydrobenzodioxane as described in step-1 of the Example-5.
  • 3-Ethoxymethyl-2,3-dihydrobenzodioxan-6-yl phenyl ketoxime was prepared from 3-ethoxymethyl-2,3-dihydrobenzodioxan-6-yl phenyl ketone as described in step-3 of the Example-5.
  • EXAMPLE 8 Preparation of 0-f4-Fluoro-3-nifrobenzoylVr3-ethoxymethyl-2.3- Dihydrobenzodioxin-6-yl1phenyl ketoxime Step 1 Initially 1 -[3-ethoxymethyl-2,3-dihydrobenzodioxan-6-yl]- 1 -phenyl methanol was prepared from 3-ethoxymethyl-6-formyl-2,3-dihydro- benzodioxane as described in step-1 of the Example-5.
  • Step 2 3-Ethoxymethyl-2,3-dihydrobenzodioxan-6-yl phenyl ketone was prepared from l-[3-ethoxymethyl-2,3-dihydrobenzodioxan-6-yl]-l -phenyl methanol as described in the step-2 of Example 5.
  • Step 3 3 -Ethoxymethyl-2,3 -dihydrobenzodioxan-6-yl phenyl ketoxime was prepared from 3 -ethoxymethyl-2,3 -dihydrobenzodioxan-6-yl phenyl ketone as described in step-3 of the Example-5;
  • Step 4 A solution of 3-ethoxymethyl-2,3-dihydrobenzodioxan-6-yl phenyl ketoxime (300mg, lmM) in dichloromethane (20mL) was treated with 4- fluoro-3-nifrobenzoyl chloride (213mg, 1.1 equiv.,) in the presence of pyridine (0.5mL) and the reaction mixture was stirred at room temperature for lh. The reaction mixture was poured into ice water and extracted with chloroform. The organic layer was washed with water, saturated sodium bicarbonate solution, brine and dried over anh. sodium sulfate.
  • Step 2 3-Ethoxymethyl-2,3-dihydrobenzodioxan-6-yl phenyl ketone was prepared from 1 -[3-ethoxymethyl-2,3-dihydrobenzodioxan-6-yl]- 1 -phenyl methanol as described in the step-2 of Example 5. Step 3
  • Step 1 Initially 1 - [3 -ethoxymethyl-2,3 -dihydrobenzodioxan-6-yl]- 1 -phenyl methanol was prepared from 3-ethoxymethyl-6-formyl-2,3-dihydrobenzo- dioxane as described in step-1 of the Example-5.
  • 3-Ethoxymethyl-2,3-dihydrobenzodioxan-6-yl phenyl ketone was prepared from l-[3-ethoxymethyl-2,3-dihydrobenzodioxan-6-yl]-l -phenyl methanol as described in the step-2 of Example 5.
  • Step l To a freshly dried magnesium turnings (1.3g, 2 equiv.,) suspended in
  • IR(neat, v max ) 3428, 3061, 3029, 2958, 2871, 1592, 1505, 1454,
  • Step 2 To a suspended solution of pyridinium chlorochromate(PCC)(5.0g, 4 equiv) in dichloromethane(80mL), 4A° molecular sieves were added followed by a solution of l-[3-butoxymethyl-2,3-dihydrobenzodioxan-6-yl]-
  • Aqueous layer was exfracted with ethyl acetate and the organic layer was washed with water, brine and dried over anh. sodium sulfate. Concenfration of the solvent provided 3.5 gm of 3-butoxymethyl-2,3-dihydrobenzodioxan- 6-yl phenyl ketoxime as solid ;
  • Step 2 3-Butoxymethyl-2,3-dihydrobenzodioxan-6-yl phenyl ketone was prepared from 1 -[3-butoxymethyl-2,3-dihydrobenzodioxan-6-yl]- 1 -phenyl methanol as described in the step-2 of Example 11.
  • Step 3 3-Butoxymethyl-2,3-dihydrobenzodioxan-6-yl phenyl ketoxime was prepared from 3-butoxymethyl-2,3-dihydrobenzodioxan-6-yl phenyl ketone as described in step-3 of the Example- 11; Step 4
  • reaction mixture was continued to stir for an additional lhr at 25°C.
  • Reaction mixture was quenched with saturated ammonium chloride solution and extracted the contents with ether.
  • Organic layer was washed with water , brine and dried over anh. sodium sulfate. Evaporation of solvent afforded
  • IR(neat, v max ) 3062, 3029, 2876, 1674, 1605, 1582, 1505, 1320,
  • 3-Ethoxymethyl-2,3-dihydrobenzodioxan-6-yl phenyl ketoxime was prepared from 3-ethoxymethyl-2,3-dihydrobenzodioxan-6-yl phenyl ketone as described in step-3 of the Example-5;
  • Step 4 To a pre-washed suspension of sodium hydride(150mg,2.0equiv., 60% oil dispersion) in tetrahydrofuran(5mL) was added a solution of 3-ethoxy- methyl-2,3-dihydrobenzodioxanyl phenyl keto oxime (300mg) dissolved in
  • IR(neat, v max ) 2976, 2872, 1603, 1508, 1273, 1222, 1118, 1030, 993,
  • Step 2 3 -Ethoxymethyl-2,3 -dihydrobenzodioxan-6-yl phenyl ketone was prepared from l-[3-ethoxymethyl-2,3-dihydrobenzodioxan-6-yl]-l -phenyl methanol as described in the step-2 of Example 5.
  • Step 4 To a pre-washed suspension of sodium hydride(100mg, 60%oil dispersion) in N,N-dimethylformamide (5mL) was added a solution of 3- ethoxymethyl-2,3-dihydrobenzo dioxanyl phenyl keto oxime (200mg) dissolved in 10 mL of N,N-dimethylformamide. Then a solution of 4- chloropyridine (300mg) dissolved in 5 mL of N,N-dimethylformamide was added to the reaction mixture and the contents were heated to 70°C for 3hrs. Reaction mixture was quenched with water and extracted with ethyl acetate. The organic extract was washed with water, brine and dried.
  • Step l Initially l-[3-ethoxymethyl-2,3-dihydrobenzodioxan-6-yl]-l -phenyl methanol was prepared from 3-ethoxymethyl-6-formyl-2,3- dihydrobenzodioxane as described in step-1 of the Example-5.
  • 3-Ethoxymethyl-2,3-dihydrobenzodioxan-6-yl phenyl ketone was prepared from 1 -[3-ethoxymethyl-2,3-dihydrobenzodioxan-6-yl]- 1 -phenyl methanol as described in the step-2 of Example 5.
  • 3-Ethoxymethyl-2,3-dihydrobenzodioxan-6-yl phenyl ketoxime was prepared from 3 -ethoxymethyl-2,3 -dihydrobenzodioxan-6-yl phenyl ketone as described in step-3 of the Example-5
  • Step 2 3 -Ethoxymethyl-2,3 -dihydrobenzodioxan-6-yl phenyl ketone was prepared from 1 -[3-ethoxymethyl-2,3-dihydrobenzodioxan-6-yl]- 1 -phenyl methanol as described in the step-2 of Example 5. Step 3
  • Step 4 To a pre-washed suspension of sodium hydride( 1 OOmg, 60%oil dispersion) in tefrahydrofuran(3mL) was added a solution of 3- ethoxymethyl-2,3-dihydrobenzodioxan-6-yl phenyl keto oxime (300mg, lmM) dissolved in 5 mL of tetrahydrofuran. Then a solution of m- chlorobenzyl bromide (390mg, 1.90mM) dissolved in 3 mL of tefrahydrofiiran was added to the reaction mixture and the contents were heated to reflux for 3hrs.
  • m- chlorobenzyl bromide 390mg, 1.90mM
  • Step 1 Initially 1 -[3-ethoxymethyl-2,3-dihydrobenzodioxan-6-yl]- 1 -phenyl methanol was prepared from 3-ethoxymethyl-6-formyl-2,3- dihydrobenzodioxane as described in step-1 of the Example-5.
  • reaction mixture was quenched with water and exfracted with ether.
  • the organic extract was washed with water, brine and dried.
  • Step 3 1 (3-Ethoxymethyl-2,3-dihydrobenzodioxan-6-yl)-2-phenyl ethanone oxime was prepared from l-(3-ethoxymethyl-2,3-dihydrobenzodioxan-6-yl)-
  • IR(KBr, v max ) 3230, 3031, 2866, 1610, 1580, 1508, 1454, 1331,
  • Step 2 (3-Benzyloxymethyl-2,3-dihydrobenzodioxan-6-yl) phenyl ketone was prepared from l-[3-benzyloxymethyl-2,3-dihydrobenzodioxan-6-yl]-l- phenyl methanol as described in the step-2 of Example 24.
  • Step 4 To a pre-washed suspension of sodium hydride (55mg,2.0 equiv., 60% oil dispersion) in tefrahydrofuran(5mL) was added a solution of 3- benzyloxymethyl-2,3-dihydrobenzodioxan-6-yl phenyl ketoxime(250mg, 0.69mM) dissolved in 10 mL of tefra-hydrofuran. Then a solution of 3- nitrobenzyl bromide(224mg,1.5 equiv.,) dissolved in 5 mL of tefrahydrofiiran was added to the reaction mixture and the contents were heated to reflux for 45min.
  • Step 2 3-Ethoxymethyl-2,3-dihydrobenzodioxan-6-yl phenyl ketone was prepared from 1 -[3-ethoxymethyl-2,3-dihydrobenzodioxan-6-yl]- 1 -phenyl methanol as described in the step-2 of Example 5.
  • Step 3 To a freshly dried magnesium turnings (300mg, 2 equiv.,) suspended in lOmL of dry ether was added a pinch of iodine followed by 3- fluorobenzyl bromide ( 1.50g,2 equiv.,) dissolved in lOmL of dry ether over a period of lOmin. and the contents were stirred at room temperature for
  • IR(neat, v max ) 3363, 3061, 3030, 2926, 1612, 1590, 1505, 1443,
  • Step 4 A solution of l-(3-ethoxymethyl-2,3-dihydrobenzodioxin-6-yl)-l -phenyl- 1- hydroxy-2-(3 -fluorophenyl) ethane (lOOmg) in dichloromethane (lOmL) was freated with m-nifrobenzoyl chloride ( O.lmL) in the presence of pyridine(O.lmL) and stirred for lhr. Reaction was quenched with water and diluted with ether. The organic layer was washed with water , sodium bicarbonate solution, brine and dried.
  • Step 2 (3-Ethoxymethyl-2,3-dihydrobenzodioxan-6-yl)phenyl ketone was prepared from 1 -[3-ethoxymethyl-2,3-dihydrobenzodioxan-6-yl]- 1 -phenyl methanol as described in the step-2 of Example 5.
  • Step 3 1 (3-Ethoxymethyl-2,3-dihydrobenzodioxin-6-yl)- 1 -phenyl- 1 - hydroxy-2-(3 -fluorophenyl) ethane was prepared from (3-ethoxymethyl-2,3- dihydrobenzodioxan-6-yl) phenyl ketone as described in step-3 of Example 26.
  • Step 4 A solution of l-(3-ethoxymethyl-2,3-dihydrobenzodioxinyl)-l-phenyl- l-hydroxy-2-(3-fluorophenyl)ethane ( lOOmg) in lOmL of benzene was treated with catalytic amount of p-toluenesulfonic acid and the contents were heated to reflux for 30min. Reaction was quenched with sodium bicarbonate solution and diluted with ethyl acetate. The organic layer was washed with water, brine and dried.
  • IR(neat, v max ) 3056, 3021, 2926, 1606, 1580, 1505, 1445, 1274, 1118, 1038, 880. 815, 782, 755, 700 cm "1 .
  • Step 2 (3-Benzyloxymethyl-2,3-dihydrobenzodioxan-6-yl) phenyl ketone was prepared from l-[3-benzyloxymethyl-2,3-dihydrobenzodioxan-6-yl]-l- phenyl methanol as described in the step-2 of Example 24. Step 3
  • IR(neat, v max ) 3563, 3061, 3030, 2926, 1614, 1588, 1505, 1447, 1275, 1252, 1096, 1037, 876, 746 699 cm "1 ;
  • Step 4 A solution of l-(3-benzyloxymethyl-2,3-dihydrobenzodioxin-6-yl)-l-phenyl- l-hydroxy-2-(3 -fluorophenyl) ethane ( lOOmg) in lOmL of benzene was treated with catalytic amount of p-toluenesulfonic acid and the contents were heated to reflux for 30min. Reaction was quenched with sodium bicarbonate solution and diluted with ethyl acetate. The organic layer was washed with water, brine and dried.
  • the aqueous extract thus obtained was acidified with hydrochloric acid and extracted with ethyl acetate.
  • the organic extract was washed with water, brine and dried over anhydrous sodium sulfate.
  • Concentration of the solvent provided the 3 -ethoxymethyl-2,3 -dihydrobenzodioxan-6-carboxylic acid (2.5g); mp : 122-124°C ;
  • Step 2 A solution of 3 -ethoxymethyl-2,3 -dihydrobenzodioxan-6-carboxylic acid( 500mg) in dichloromethane( lOmL) was cooled to 0°C and added ImL of N,N-dimethylformamide. Then oxalyl chloride (0.8mL) was added to the reaction mixture and stirred at room temperature for 16hrs. The solvents were removed under vacuum to get the corresponding acid chloride which was subjected to next reaction as such.
  • Step 3 To a solution of 4-methoxy aniline(156mg, 1.26mM) and diisopropylethylamine (0.5mL) dissolved in 5mL of 1 ,2-dichloromethane, a solution of acid chloride (300mg, 1.26mM,obtained from the above step-2) in 5mL of dichloromethane was added and stirred at room temperature for 16hr. The reaction was quenched with water and extracted with chloroform. The organic layer was washed with water, 5 % HCI and brine solution.
  • 3-Ethoxymethyl-2,3-dihydrobenzodioxan-6-carboxylic acid was prepared from 3 -ethoxymethyl-6-formyl-2,3 -dihydrobenzodioxane as described in step- 1 of Example 30.
  • Step 3 To a solution of 2,6-dichloroaniline (200mg, 1 equiv.,) and triethyl amine (0.5mL) dissolved in 6mL of tefrahydrofuran a solution of acid chloride (300mg, 1.26mM,obtained from the above step-2) in 5mL of tefrahydrofuran was added and stirred at room temperature for 16h. The reaction was quenched with water and extracted with chloroform. The organic layer was washed with water, 5%HC1 and brine solution.
  • IR(KBr, v max ) 3237, 2974, 2884, 1645, 1610, 1586, 1495, 1439, 1320, 1280,1200,1133,1115, 1099, 1028, 818, 772, 763 cm "1 ;
  • Step 2 A solution of 3 -ethoxymethyl-2,3 -dihydrobenzodioxan-6-carboxylic acid( 300mg, 1.26mM) in freshly distilled thionyl chloride (5mL)was heated to reflux temperature for 1.5h. The excess thionyl chloride was removed under vacuum to get the corresponding acid chloride which was subjected to next reaction as such. Ste ⁇ 3
  • Step 1 3 -Ethoxymethyl-2,3 -dihydrobenzodioxan-6-carboxylic acid was prepared from 3 -ethoxymethyl-6-formyl-2,3 -dihydrobenzodioxane as described in step- 1 of Example 30.
  • Step 1 To a solution of 3-butoxymethyl-6-formyl-2,3-dihydrobenzo- dioxane(5g, 20 mM) in 150mL of acetone was added potassium permanganate (7g,2equiv.,) and stirred at room temperature under nifrogen atmosphere for 16hrs. At the end, acetone was removed and diluted with potassium permanganate (7g,2equiv.,) and stirred at room temperature under nifrogen atmosphere for 16hrs. At the end, acetone was removed and diluted with
  • 6-carboxylic acid( 450mg) in freshly distilled thionyl chloride (lOmL) was heated to reflux temperature for 1.5hr.
  • the excess thionyl chloride was removed under reduced pressure to get the corresponding acid chloride which was subjected to next reaction as such.
  • Step 3 To a solution of 2,5-dichloroaniline (243mg, 1.2 equiv.,) and N,N- diiso-propylethyl amine (0.5mL) dissolved in lOmL of tefrahydrofuran, a solution of acid chloride (400mg, obtained from the above step-2) in tefrahydrofuran(5mL) was added and stirred at room temperature for 16hr. The reaction was quenched with water and extracted with diethyl ether. The organic layer was washed with water, 5% HCI and brine solution. Concenfration of the solvent followed by purification of the residue over column chromatography using 8% acetone-pet. ether has provided N-(2,5- dichlorophenyl)-3-(m-fluorobenzyloxymethyl)-2,3-dihydrobenzodioxinyl-6- carbox-amide (150mg);
  • IR(KBr, v max ) 3390,3272, 3102, 2925, 1646, 1612, 1582, 1503, 1407, 1293, 1265, 1191, 1091, 1046, 915, 810 ,749 cm "1 .
  • Step 2 A solution of 3 -ethoxymethyl-2,3 -dihydrobenzodioxan-6-carboxylic acid (350 mg) in benzene(5mL) was added freshly distilled thionyl chloride (5mL) and the reaction mixture was heated to reflux temperature for 6hrs. The solvents and the excess thionyl chloride were removed under vacuum to get the corresponding acid chloride which was subjected to next reaction as such.
  • 3-Ethoxymethyl-2,3-dihydrobenzodioxan-6-yl phenyl ketoxime was prepared from 3 -ethoxymethyl-2,3 -dihydrobenzodioxan-6-yl phenyl ketone as described in step-3 of the Example-5;
  • Step 4 To a solution of m-nifroaniline( 276mg, 2 equiv.,) and diisopropylethylamine (0.5mL) dissolved in 5 mL of dichloromethane cooled to -30°C, was added a solution of triphosgene (230mg,0.8mM) in 5 mL of dichloror- methane and the contents were stirred for 6h under N 2 atmosphere by allowing the temperature to come to r.t.
  • triphosgene 230mg,0.8mM
  • 3 -Ethoxymethyl-2,3 -dihydrobenzodioxan-6-yl phenyl ketone was prepared from 1 -[3-ethoxymethyl-2,3-dihydrobenzodioxan-6-yl]- 1 -phenyl methanol as described in the step-2 of Example 5.
  • Step 3 3-Ethoxymethyl-2,3-dihydrobenzodioxan-6-yl phenyl ketoxime was prepared from 3 -ethoxymethyl-2,3 -dihydrobenzodioxan-6-yl phenyl ketone as described in step-3 of the Example-5;
  • 3-Ethoxymethyl-2,3-dihydrobenzodioxan-6-yl phenyl ketone was prepared from 1 -[3-ethoxymethyl-2,3-dihydrobenzodioxan-6-yl]- 1 -phenyl methanol as described in the step-2 of Example 5.
  • Step 3 3-Ethoxymethyl-2,3-dihydrobenzodioxan-6-yl phenyl ketoxime was prepared from 3 -ethoxymethyl-2,3 -dihydrobenzodioxan-6-yl phenyl ketone as described in step-3 of the Example-5. Step 4
  • Step l Initially l-[3-(N,N-diethylaminomethyl)-2,3-dihydrobenzodioxin-6- yl]-l-(3-chlorophenyl) methanol was prepared from 3-(N,N-diethylamino- methyl)-6-formyl-2,3-dihydrobenzodioxane as described in step 1 of
  • Step 2 To a pre-washed suspension of sodium hydride (80mg, 2 equiv., 60% oil dispersion) in THF (5mL) was added a solution of l-[3-(N,N-diethyl- amino-methyl)-2,3-dihydrobenzodioxin-6-yl]- 1 -(3 -chlorophenyl) methanol
  • Step l Initially l-[3-(N,N-diethylaminomethyl)-2,3-dihydrobenzodioxin-6- yl]-l -(3 -chlorophenyl) methanol was prepared from 3-(N,N- diethylaminomethyl)-6-formyl-2, 3 -dihydrobenzodioxane as described in step 1 of Example 43.
  • Step 2 To a suspended solution of pyridinium dichromate (PDC) (4.6g, 1.1 equiv.,) in dichloromethane (50mL) was added a solution of l-[3-(N,N- diethylaminomethyl)-2,3-dihydrobenzodioxin-6-yl]-l-(3-chlorophenyl) methanol (4.0g, 0.011 lmol) dissolved in dichloromethane (30mL) at ice temperature. The reaction mixture was stirred for 2h by warming it to room temperature and quenched with lOmL of dry ether. The organic layer was decanted and filtered through a celite pad.
  • PDC pyridinium dichromate
  • IR (neat, v max ): 2970, 2927, 2873, 1581, 1506, 1429, 1316, 1272,
  • [3-(N,N-diethylaminomethyl)-2,3-dihydrobenzodioxin-6-yl]-3- chlorophenyl methanone oxime was prepared from l-[3-(N,N- diethylaminomethyl)-2,3-dihydro benzodioxin-6-yl]- 1 -(3 -chlorophenyl) methanone as described in step 3 of Example 5.
  • Step 1 To a solution of n-butyl lithium (34.2mL, 2 equiv., 15% solution in n- hexane) cooled to -78°C was added a solution of 2-bromopyridine (12.56g, 2 equiv.,) in THF (20mL). The contents were stirred for lOmin. at -78°C and was added drop wise a solution of 3-ethoxymethyl-6-formyl-2,3- dihydrobenzodioxane (9.0g, 0.04mol) (Intermediate 1) in THF (25mL) over a period of lOmin. The reaction mixture was stirred at -78°C for 30min.
  • Step 2 To a pre-washed suspension of sodium hydride (48mg, 1.5 equiv., 60% oil dispersion) in THF (3mL) was added a solution of l-(3- ethoxymethyl-2,3 -dihydrobenzodioxin-6-yl)- 1 -(pyrid-2-yl) methanol (200mg, 0.66mmol) in 3mL of THF. Then a solution of 4- fluorobenzylbromide (0.149g, 1.2 equiv.,) in THF (4mL) was added to the above reaction mixture and the contents were refluxed for lh. The reaction mixture was quenched with water and extracted with ether.
  • Step 1 To a solution of n-butyl lithium (34.2mL, 2 equiv., 15% solution in n- hexane) cooled to -78°C was added a solution of 2-bromopyridine (12.56g, 2 equiv.,) in THF (20mL). The contents were stirred for lOmin. at -78°C and to this was added drop wise a solution of 3-butoxymethyl-6-formyl-2,3- dihydrobenzodioxane (lO.Ogm, 0.040mol) (Intermediate 2) in THF (25mL) over a period of lOmin. The reaction mixture was stirred at -78°C for 30min.
  • IR (neat, v max ): 2933, 2957, 2871, 1590, 1505, 1467, 1434, 1275,
  • Step 1 Initially 1 -(3-butoxymethyl-2,3-dihydrobenzodioxin-6-yl)- 1 -(pyrid-2- yl) methanol was prepared from 3-butoxymethyl-6-formyl-2,3- dihydrobenzodioxane (Intermediate 2) as described in step 1 of Example 49.
  • Step 1 Initially 1 -(3-ethoxymethyl-2,3-dihydrobenzodioxin-6-yl)- 1 -(pyrid-2- yl) methanol was prepared from 3-ethoxymethyl-6-formyl-2,3- dihydrobenzodioxane (Intermediate 2) as described in step 1 of Example 48.
  • Step 2 To a suspended solution of pyridinium dichromate (PDC) (2.29g, 1.0 equiv.,) in dichloromethane (25mL) was added a solution of l-(3-ethoxy- methyl-2,3-dihydrobenzodioxin-6-yl)-l-(pyrid-2-yl) methanol (2.0g, 0.0332mol) in dichloromethane (lOmL) at ice temperature. The reaction mixture was then stirred at room temperature for 30min. and quenched with ether. The organic layer was decanted and filtered through a small pad of celite.
  • PDC pyridinium dichromate
  • IR (neat, v max ): 3055, 2976, 2929, 2876, 1658, 1604, 1580, 1504, 1435, 1308, 1274, 1145, 1118, 1093, 1032, 995, 907, 830, 804, 748, 698 cm “ ';
  • Step 4 To a pre-washed suspension of sodium hydride (50mg, 2 equiv., 60% oil dispersion) in N,N-dimethylformamide (4mL) was added a solution of 1 - [3 -ethoxymethyl-2,3 -dihydrobenzo dioxin-6-yl]- 1 -(pyrid-2-yl)methanone oxime (200mg, 0.95mmol) in N,N-dimethylformamide (5mL). Then a solution of 4-fluorobenzylbromide (242mg, 2.0 equiv.,) in N,N- dimethylformamide (3mL) was added to the above reaction mixture and the contents were heated at 60°C for lh.
  • Step 1 Initially 1 -(3-ethoxymethyl-2,3-dihydrobenzodioxin-6-yl)- 1 -(pyrid-2- yl) methanol was prepared from 3-ethoxymethyl-6-formyl-2,3- dihydrobenzodioxane (Intermediate 1) as described in step 1 of Example 48.
  • Step 2 1 -[3 -Ethoxymethyl-2,3 -dihydrobenzodioxin-6-yl]- 1 -(pyrid-2- yl)methanone was prepared from l-(3-ethoxymethyl-2,3- dihydrobenzodioxin-6-yl)-l-(pyrid-2-yl) methanol as described in step 2 of Example 51.
  • Step 3 To freshly dried magnesium turnings (96mg, 4 equiv.,) suspended in dry ether (lOmL) was added a pinch of iodine followed by a solution of 3- chlorobenzylbromide (0.83g, 4 equiv.,) in dry ether (lOmL) over a period of lOmin. The contents were stirred for 30min. at room temperature so that the magnesium is completely consumed to form Grignard reagent.
  • Step 1 Initially 1 -(3 -butoxymethyl-2,3 -dihydrobenzodioxin-6-yl)- 1 -(pyrid-2- yl) methanol was prepared from 3-butoxymethyl-6-formyl-2,3- dihydrobenzodioxane (Intermediate 2) as described in step 1 of Example 49.
  • Step 1 Initially 1 -(3-butoxymethyl-2,3-dihydrobenzodioxin-6-yl)- 1 -(pyrid-2- yl) methanol was prepared from 3-butoxymethyl-6-formyl-2,3- dihydrobenzodioxane (Intermediate 2) as described in step 1 of Example 49.
  • Step 4 A solution of l-(3-butoxymethyl-2,3-dihydrobenzodioxin-6-yl)-l- hydroxy- 1 -(pyrid-2-yl)-2-(3-chlorophenyl)ethane (150mg, 0.33mmol) in benzene (lOmL) was treated with p-toluenesulphonic acid ( 25 lmg, 4 equiv.,) and the contents were heated to reflux for 4h. The reaction was quenched with saturated sodium bicarbonate solution and diluted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate, and brine and dried over anhydrous sodium sulfate.
  • Step 2 A solution of 3 -cyclopropylmethoxymethyl-2,3 -dihydrobenzodioxane-6- carboxylic acid (250mg, 0.946mmol) in freshly distilled thionyl chloride (5mL) was heated to reflux temperature for 1.5h. The excess thionyl chloride was removed under vacuum to get the corresponding acid chloride which was subjected the next reaction as such. Step 3
  • Step 2 Initially 3-cyclopropylmethoxymethyl-2,3-dihydrobenzodioxane-6- carboxylic acid chloride was prepared from 3-cyclopropylmethoxymethyl- 2,3-dihydrobenzodioxane-6-carboxylic acid as described in steps 2 of Example 57.
  • Step 3 To a pre-washed suspension of sodium hydride (11 lmg, 1.0 equiv., 60% oil dispersion) in THF (5mL) was added drop wise a solution of 4- amino-3,5-dichloropyridine (189mg, 1.0 equiv.) in THF (5mL) at -10°C. A pre-cooled solution of above acid chloride (from step 1) in THF (5mL) was added, all at once, to the reaction mixture and the contents were stirred at - 10°C for 30min. The reaction was quenched with brine, diluted with water and extracted with ethyl acetate. The organic layer was washed with water, 5
  • the organic layer was washed with water, 5% HCI and brine solution.
  • IR (KBr, vmax): 3339, 3041, 2944, 1650, 1612, 1534, 1505, 1407, 1335, 1286, 1173, 1115, 970, 832, 755, 528 cm "1 ;
  • Step 1 Initially 3-methanesulfonyloxymethyl-6-formyl-2,3-dihydrobenzo- dioxane was prepared from 3-hydroxymethyl-6-formyl-2,3- dihydroxybenzodioxane as described in step 2 of Intermediate 4.
  • 6-carboxylic acid 150mg, 0.52mmol
  • freshly distilled thionyl chloride (2mL) in dry benzene (2mL) was heated to reflux temperature for 2h.
  • the excess thionyl chloride/benzene was removed under vacuum to get the corresponding acid chloride which was subjected the next reaction as such.
  • Step 3 A solution of 3-tert.butyldimethylsilyloxymethyl-2,3- dihydrobenzodioxane-6-carboxylic acid (1.4g, 4.43mmol) and freshly distilled thionyl chloride (5mL) in dry benzene (5mL) was heated to reflux temperature for 2h. The excess thionyl chloride/benzene was removed under vacuum to get the corresponding acid chloride which was subjected the next reaction as such.

Abstract

Composé correspondant à la formule générale (I) et procédé pour préparer et utiliser le composé correspondant à la formule (I).
PCT/US2002/007315 2001-03-13 2002-03-12 Nouveaux composes heterocycliques utiles dans le traitement des troubles allergiques inflammatoires; procede de leur preparation et compositions pharmaceutiques les contenant WO2002072567A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002306687A AU2002306687A1 (en) 2001-03-13 2002-03-12 Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN240/MUM/2001 2001-03-13
IN240MU2001 2001-03-13

Publications (2)

Publication Number Publication Date
WO2002072567A2 true WO2002072567A2 (fr) 2002-09-19
WO2002072567A3 WO2002072567A3 (fr) 2002-11-28

Family

ID=11097228

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2002/007315 WO2002072567A2 (fr) 2001-03-13 2002-03-12 Nouveaux composes heterocycliques utiles dans le traitement des troubles allergiques inflammatoires; procede de leur preparation et compositions pharmaceutiques les contenant

Country Status (2)

Country Link
AU (1) AU2002306687A1 (fr)
WO (1) WO2002072567A2 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004037805A1 (fr) * 2002-10-23 2004-05-06 Glenmark Pharmaceuticals Ltd. Nouveaux composes tricycliques utiles pour traiter les troubles inflammatoires et allergiques, procede de preparation de ces composes et compositions pharmaceutiques les contenant
WO2004069831A1 (fr) * 2003-02-10 2004-08-19 Glenmark Pharmaceuticals Ltd. Composes tricycliques utiles dans le traitement de troubles inflammatoires et allergiques, et procede de preparation de ces composes
WO2004111044A1 (fr) * 2003-06-17 2004-12-23 Glenmark Pharmaceuticals Ltd. Composes tricycliques efficaces dans le traitement des affections inflammatoires et allergiques : leur procede de preparation
US7223789B2 (en) 2003-04-11 2007-05-29 Glenmark Pharmaceuticals S.A. Heterocyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them
US7563900B2 (en) 2004-10-13 2009-07-21 Glenmark Pharmaceuticals S.A. Process for the preparation N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methane sulfonamido-dibenzo[b,d]furan-1-carboxamide
US7943634B2 (en) 2004-12-17 2011-05-17 Glenmark Pharmaceuticals S.A. Substituted benzo[4,5]furo[3,2-c]pyridine derivatives as PDE 4 inhibitors
US8129401B2 (en) 2004-12-17 2012-03-06 Glenmark Pharmaceuticals S.A. Heterocyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them
US10029995B2 (en) 2015-09-03 2018-07-24 Forma Therapeutics, Inc. [6,6] fused bicyclic HDAC8 inhibitors
US11724999B2 (en) 2018-01-24 2023-08-15 Oxford University Innovation Limited Inhibitors of RAS-effector protein interactions

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1193637A (fr) * 1957-01-08 1959-11-04 Rhone Poulenc Sa Nouveaux dérivés acylés et aminés du benzodioxanne
US3157674A (en) * 1963-04-30 1964-11-17 Ciba Geigy Corp 2-(cycloaliphatic-alkyl-aminomethyl)-benzodioxanes
DE1518042A1 (de) * 1965-11-11 1969-06-12 Merck Ag E Verfahren zur Herstellung von 1,4-Benzodioxanderivaten
DE2840454A1 (de) * 1978-09-16 1980-04-03 Madaus & Co Dr Alkaliumsetzungsprodukte eines acetonisolierungsproduktes aus phytolacca- arten, deren herstellung und arzneimittel
GB2046259A (en) * 1979-03-20 1980-11-12 Kyowa Hakko Kogyo Kk Amino-alcohol derivatives and pharmaceutical compositions containing them
WO1992018494A1 (fr) * 1991-04-19 1992-10-29 Ciba-Geigy Ag Esters de methyle ou d'acide aldimino- ou cetimino-oxy-orthotolylacrylique, procede de fabrication et fongicides contenant ces composes

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1193637A (fr) * 1957-01-08 1959-11-04 Rhone Poulenc Sa Nouveaux dérivés acylés et aminés du benzodioxanne
US3157674A (en) * 1963-04-30 1964-11-17 Ciba Geigy Corp 2-(cycloaliphatic-alkyl-aminomethyl)-benzodioxanes
DE1518042A1 (de) * 1965-11-11 1969-06-12 Merck Ag E Verfahren zur Herstellung von 1,4-Benzodioxanderivaten
DE2840454A1 (de) * 1978-09-16 1980-04-03 Madaus & Co Dr Alkaliumsetzungsprodukte eines acetonisolierungsproduktes aus phytolacca- arten, deren herstellung und arzneimittel
GB2046259A (en) * 1979-03-20 1980-11-12 Kyowa Hakko Kogyo Kk Amino-alcohol derivatives and pharmaceutical compositions containing them
WO1992018494A1 (fr) * 1991-04-19 1992-10-29 Ciba-Geigy Ag Esters de methyle ou d'acide aldimino- ou cetimino-oxy-orthotolylacrylique, procede de fabrication et fongicides contenant ces composes

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ALEJANDRA G. SUAREZ: "ALCL3-DMA REAGENT" TETRAHEDRON LETTERS., vol. 40, 1999, pages 3523-6, XP004162326 ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM., NL ISSN: 0040-4039 *
V. THIÉRY ET AL.: "CONVENIENT SYNTHESIS OF 2-SUBST. 6- OR 7-ACYLATED 1,4-BENZODIOXIN" TETRAHEDRON., vol. 51, no. 9, 1995, pages 2619-28, XP002214666 ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM., NL ISSN: 0040-4020 *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AP2021A (en) * 2002-10-23 2009-08-03 Glenmark Pharmaceuticals Ltd Novel tricyclic compounds useful for the treatmentof inflammatory and allergic disorders: Process f or their preparation and pharmaceutical compositions containing them
US7238725B2 (en) 2002-10-23 2007-07-03 Glenmark Pharmaceuticals Ltd. Tricyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them
EA010408B1 (ru) * 2002-10-23 2008-08-29 Гленмарк Фармасьютикалс Лтд. Трициклические соединения для лечения воспалительных и аллергических нарушений, способы их приготовления и содержащие их фармацевтические составы
WO2004037805A1 (fr) * 2002-10-23 2004-05-06 Glenmark Pharmaceuticals Ltd. Nouveaux composes tricycliques utiles pour traiter les troubles inflammatoires et allergiques, procede de preparation de ces composes et compositions pharmaceutiques les contenant
WO2004069831A1 (fr) * 2003-02-10 2004-08-19 Glenmark Pharmaceuticals Ltd. Composes tricycliques utiles dans le traitement de troubles inflammatoires et allergiques, et procede de preparation de ces composes
US7223789B2 (en) 2003-04-11 2007-05-29 Glenmark Pharmaceuticals S.A. Heterocyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them
US7384962B2 (en) 2003-04-11 2008-06-10 Glenmark Pharmaceuticals S.A. Heterocyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them
US7393846B2 (en) 2003-04-11 2008-07-01 Glenmark Pharmaceuticals, S.A. Heterocyclic compounds useful for the treatment of inflammatory and allergic disorders
WO2004111044A1 (fr) * 2003-06-17 2004-12-23 Glenmark Pharmaceuticals Ltd. Composes tricycliques efficaces dans le traitement des affections inflammatoires et allergiques : leur procede de preparation
US7563900B2 (en) 2004-10-13 2009-07-21 Glenmark Pharmaceuticals S.A. Process for the preparation N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methane sulfonamido-dibenzo[b,d]furan-1-carboxamide
US7943634B2 (en) 2004-12-17 2011-05-17 Glenmark Pharmaceuticals S.A. Substituted benzo[4,5]furo[3,2-c]pyridine derivatives as PDE 4 inhibitors
US8129401B2 (en) 2004-12-17 2012-03-06 Glenmark Pharmaceuticals S.A. Heterocyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them
US10029995B2 (en) 2015-09-03 2018-07-24 Forma Therapeutics, Inc. [6,6] fused bicyclic HDAC8 inhibitors
US10370343B2 (en) 2015-09-03 2019-08-06 Forma Therapeutics, Inc. [6,6] Fused bicyclic HDAC8 inhibitors
US10829460B2 (en) 2015-09-03 2020-11-10 Valo Early Discovery, Inc. [6,6] fused bicyclic HDAC8 inhibitors
US11414392B2 (en) 2015-09-03 2022-08-16 Valo Health, Inc. [6,6] fused bicyclic HDAC8 inhibitors
US11724999B2 (en) 2018-01-24 2023-08-15 Oxford University Innovation Limited Inhibitors of RAS-effector protein interactions

Also Published As

Publication number Publication date
WO2002072567A3 (fr) 2002-11-28
AU2002306687A1 (en) 2002-09-24

Similar Documents

Publication Publication Date Title
EP1620429B1 (fr) Nouveaux composes heterocycliques pour le traitement des affections inflammatoires et allergiques, leur procede de preparation et compositions pharmaceutiques les contenant
RU2135498C1 (ru) Пиразоло- и пирролопиридины
KR101060016B1 (ko) 11-베타-히드록시스테로이드 데히드로게나제 1의 억제제로서의 피페리디닐 치환 피롤리디논
US6514996B2 (en) Derivatives of benzofuran or benzodioxole
US6020339A (en) Aryl furan derivatives as PDE IV inhibitors
DE69534164T2 (de) Tri-substituierte phenyl-derivate verwendbar als pde iv hemmer
JP3165401B2 (ja) アミノメチレンで置換した非芳香族複素環式化合物及びサブスタンスｐのアンタゴニストとしての使用
JP2944048B2 (ja) 二環式テトラヒドロピラゾロピリジン
EP0901482B1 (fr) Carboxamides de benzofurane et leurs utilisations therapeutiques
JP3554337B2 (ja) インダゾール誘導体、およびホスホジエステラーゼ（ｐｄｅ）タイプ４と腫瘍壊死因子（ｔｎｆ）産生の阻害剤としてのインダゾール誘導体の使用
JP5101602B2 (ja) １１−β−ヒドロキシステロイドデヒドロゲナーゼ１の阻害剤
DE60317918T2 (de) Tricyclische verbindungen zur behandlung von entzündlichen und allergischen erkrankungen verfahren zu deren herstellung und sie enthaltende pharmazeutische zusammensetzungen
US6034089A (en) Aryl thiophene derivatives as PDE IV inhibitors
JP2009535356A (ja) １１−β−ヒドロキシステロイドデヒドロゲナーゼ１の阻害剤
JP2009535357A (ja) １１−β−ヒドロキシステロイドデヒドロゲナーゼ１の阻害剤
WO2010058846A1 (fr) 4,6-diaminonicotinamide
CN1329609A (zh) 用作多巴胺d3受体调制剂(精神抑制药)的四氢苯并氮杂䓬衍生物
US5773467A (en) Benzofuran sulphonanmides
CN112654608A (zh) 具有脲结构的稠环化合物
WO2002072567A2 (fr) Nouveaux composes heterocycliques utiles dans le traitement des troubles allergiques inflammatoires; procede de leur preparation et compositions pharmaceutiques les contenant
WO2004111044A1 (fr) Composes tricycliques efficaces dans le traitement des affections inflammatoires et allergiques : leur procede de preparation
WO2004016596A1 (fr) Composes condenses heterocycliques utilises comme inhibiteurs de pde-iv dans le traitement de troubles inflammatoires et allergiques
EP1257548B1 (fr) Carboxamides de benzofurane et leur utilisation therapeutique
WO2002014277A1 (fr) Composes de biphenylcarboxamidoisoindoline, procedes de preparation de ceux-ci et produits intermediaires destines a la synthese de ceux-ci
WO2004089939A1 (fr) Derives de furan condense utilises en tant qu'antagonistes d'adenosine

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
AK Designated states

Kind code of ref document: A3

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase in:

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP